citalopram escitalopram Lexapro
Effects of haloperidol, clozapine and citalopram on messenger RNA levels of chromogranins A and B and secretogranin II in various regions of rat brain.

Kroesen S, Marksteiner J, Mahata SK, Mahata M, Fischer-Colbrie R, Saria A, Kapeller I, Winkler H.

Department of Pharmacology, University of Innsbruck, Austria.

We have measured the messenger RNA levels of chromogranins A and B and secretogranin II in various brain regions of rats subchronically treated with various antipsychotic drugs. Since, as shown previously, the messenger RNA levels of these peptides are increased when neurons are stimulated, we hoped to identify by this approach those nuclei which are subchronically influenced by these drugs. The drugs chosen were the neuroleptic halperidol, a blocker of dopamine receptors, the atypical antipsychotic clozapine, which in addition to blocking dopamine receptors also blocks those for serotonin, and citalopram, a specific serotonin reuptake inhibitor. In agreement with previous data on neuropeptide messenger RNAs, we found in the dorsolateral striatum an increase of the secretogranin II messenger RNA levels after haloperidol and a much smaller one after clozapine. In the nucleus accumbens and in the bed nucleus of the stria terminalis, both compounds had a comparable positive effect. These differential effects can be attributed to a different action of these drugs on dopamine receptor subtypes. In the zona incerta, clozapine decreased the secretogranin II and chromogranin A message, whereas in the dorsal raphe it led to an increase. On the other hand, citalopram induced exactly the opposite effects in these two brain regions. This phenomenon can be explained by the differential interaction of these drugs with serotonergic mechanisms. Additional, relatively small changes of the mRNAs were seen in several other brain regions. These results establish that changes in the mRNA levels of the chromogranins are good indicators for the effect of drugs on certain brain nuclei. The concomitant action of haloperidol and clozapine on the limbic regions, i.e. the nucleus accumbens and the bed nucleus of the stria terminalis, points to these brain regions for the antipsychotic action of these two neuroleptics.

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Simplified high-performance liquid chromatographic method for the determination of citalopram and desmethylcitalopram in serum without interference from commonly used psychotropic drugs and their metabolites.

Olesen OV, Linnet K.

Department of Biological Psychiatry, Psychiatric Hospital, Aarhus University Hospital, Risskov, Denmark.

A simplified method for the determination of racemic citalopram and its main metabolite desmethylcitalopram in serum using HPLC was developed. The compounds were extracted with heptane-isoamyl alcohol (98:2) and subsequently transferred into phosphate buffer pH 2.5 for direct injection into the HPLC apparatus. The analytes were separated with an acetonitrile-phosphate buffer, pH 2.5-tetraethylamine mobile phase on a C18 column and measured by UV detection at 240 nm. Within the typical range of serum concentrations (30-100 ng/ml) the inter-day variation was < 6% for both compounds. Possible analytical interference from a number of commonly coadministered psychoactive drugs and their metabolites was studied by extracting sera from patients receiving these drugs. Interference was not a problem for the developed method.

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citalopram escitalopram Lexapro
Pharmacological characterization of the cloned human 5-hydroxytryptamine transporter.

Agnel M, Esnaud H, Langer SZ, Graham D.

Synthelabo Recherche, Rueil Malmaison, France.

We performed an extensive pharmacological study of the 5-hydroxytryptamine (5-HT) transporter polypeptide cloned from human placenta. Transient expression of this 630 amino acid polypeptide in HeLa cells led to saturable 5-HT uptake activity (Km = 858 nM). This 5-HT uptake was blocked by selective 5-HT inhibitors, such as citalopram, litoxetine, sertraline, and indalpine, with Ki values in the low nanomolar range, and it exhibited a pharmacological profile similar to that found in rat brain. [3H]Citalopram binding to membrane preparations of the transfected cells occurred to a single class of high-affinity binding sites (Kd = 5.3 nM) and was potently inhibited by selective 5-HT uptake inhibitors. The pharmacological profile of [3H]citalopram binding to these transfected cells showed a good correlation with that of [3H]paroxetine binding to the rat cerebral cortical 5-HT transporter (r = 0.79). These data confirm that the full pharmacological characteristics of the 5-HT transport system are conferred by the expression of the 630 amino acid human placental 5-HT transporter polypeptide. [3H]Citalopram should, therefore, provide a useful probe for more insights at a molecular level into this cloned 5-HT transport system.

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The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes.

Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y.

Department of Clinical Pharmacy, Showa University, Tokyo, Japan.

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

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Adaptive changes in the reactivity of 5-HT1A and 5-HT2 receptors induced in rat frontal cortex by repeated imipramine and citalopram.

Bobula B, Tokarski K, Zahorodna A, Hess G.

Department of Physiology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343 Krakow, Poland.

Using extracellular ex vivo recording we studied changes in the reactivity of rat frontal cortical neurons to the 5-HT(1A), 5-HT(2) and 5-HT(4) receptor agonists (+/-)-2-dipropyloamino-8-hydroxy-1,2,3,4-tetrahydronaphtalene hydrobromide (8-OH-DPAT), (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and zacopride, respectively, induced by a repeated treatment with imipramine or citalopram. Rats were treated with imipramine or citalopram for 14 days (10 mg/kg p.o.) twice daily. Frontal cortical slices were prepared 2 days after the last drug administration. Spontaneous epileptiform discharges were induced in slices by perfusion with a medium devoid of Mg(2+) ions and with added picrotoxin (30 microM). While the application of 2 microM 8-OH-DPAT resulted in a reversible decrease of the discharge frequency, in the presence of DOI (1 microM) or zacopride (5 microM), the discharge frequency was increased. Both repeated imipramine and citalopram enhanced the effect of the activation of 5-HT(1A) receptor and attenuated the effect related to 5-HT(2) receptor activation, while the effect of the activation of 5-HT(4) receptor remained unchanged. Moreover, imipramine, but not citalopram, induced a reduction of epileptiform discharge frequency and an increase of the time of occurrence of epileptiform activity. These data indicate that antidepressants enhance the 5-HT-mediated inhibition in neuronal circuitry of the frontal cortex.

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Effects of acute and repeated administration of citalopram on extracellular levels of serotonin in rat brain.

Moret C, Briley M.

Centre de Recherche Pierre Fabre, Castres, France.

The effects of acute (2 days) and repeated (21 days) administration (50 mg/kg in the diet) of the selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitor, citalopram, on extracellular levels of 5-HT and their modulation by terminal autoreceptors in the hypothalamus of freely moving rats were compared in vivo by microdialysis. When studied without washout, extracellular levels of 5-HT were increased by both acute and repeated citalopram administration. In rats treated repeatedly, extracellular 5-HT levels were 43% (but not significantly) greater than in those treated acutely. Extracellular levels of 5-HT in control and citalopram-treated rats were similar when measured after 24 h washout. The enhancing effect of non-selective serotonergic autoreceptor antagonists, methiothepin (100 microM) or 1-(1-naphthyl)piperazine (NP) (10 microM), administered through the microdialysis probe, after 24 h washout, was similar in both control and chronically treated groups. These results suggest that repeated administration of citalopram followed by a washout of 24 h does not lead to desensitization of the terminal autoreceptor as measured in vivo in contrast to the effects we have shown previously in vitro. In rats treated chronically with citalopram without washout, methiothepin had a greater maximal effect on 5-HT outflow in comparison to rats receiving acute citalopram treatment. This finding suggests that a 5-HT autoreceptor antagonist or a combination of such a drug with a 5-HT uptake inhibitor would produce a greater increase of extracellular levels of 5-HT in hyposerotonergic states such as depression.

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The effect of age and concomitant treatment with other psychoactive drugs on serum concentrations of citalopram measured with a nonenantioselective method.

Leinonen E, Lepola U, Koponen H, Kinnunen I.

Kuopio Psychiatric Research Clinic, Kuopio, Finland.

We measured citalopram and desmethylcitalopram concentrations in serum from 169 psychiatric patients, who were treated with common therapeutic drug doses. Altogether 202 serum samples were assayed by a nonenantioselective high-performance liquid chromatography (HPLC) method. The results indicate that the kinetic variability (maximum concentration/minimum concentration) in dose- and weight-related serum citalopram (10.6-fold) and desmethylcitalopram (7.2-fold) is large even during monotherapy. Log serum citalopram (r = 0.36, p < 0.05) and desmethylcitalopram (r = 0.51, p < 0.01) concentrations of individual patients increased significantly with increasing drug doses. Dose- and weight-related (calculated as mg/kg dose basis) log serum citalopram (r = 0.29) but not desmethylcitalopram (r = 0.06) concentrations increased with aging (p < 0.001). No sex-related differences were found. Nineteen patients (19 samples) had concomitant treatment with neuroleptics, 84 patients (101 samples) with benzodiazepines, and 18 patients (28 samples) with tricyclic antidepressants. The concentrations in these patients were compared with those of 48 nonsmoking patients (54 samples) without any concomitant psychotropic drug treatment. None of the single neuroleptics alone had a significant effect on dose- and weight-related serum citalopram or desmethylcitalopram concentrations. However, citalopram concentrations increased by 121% (338 +/- 165 vs. 747 +/- 505, mean +/- SD; p < 0.01) and desmethylcitalopram by 85% (124 +/- 53 vs. 229 +/- 138; p < 0.05) when neuroleptics were pooled. Among single benzodiazepines, only alprazolam increased serum citalopram (338 +/- 165 vs. 391 +/- 267; p < 0.01) and desmethylcitalopram (124 +/- 53 vs. 186 +/- 175; p < 0.01) concentrations. When all the benzodiazepines were pooled, they still increased the serum concentration of the parent drug by 23% (338 +/- 165 vs. 414 +/- 303; p < 0.05) and those of the metabolite by 47% (124 +/- 53 vs. 182 +/- 163; p < 0.01). In patients who were simultaneously treated with clomipramine, serum citalopram (338 +/- 165 vs. 655 +/- 409; p < 0.001) and desmethylcitalopram (124 +/- 53 vs. 435 +/- 347; p < 0.001) concentrations were consistently higher than those of the controls. Even when the tricyclic antidepressants were pooled, they increased citalopram concentrations by 44% (338 +/- 165 vs. 486 +/- 312; p < 0.001) and desmethylcitalopram concentrations by 111% (124 +/- 53 vs. 261 +/- 260; p < 0.001). The results suggest that interindividual variability in serum citalopram concentrations is pronounced and that increased serum citalopram levels are related to advancing age and concomitant treatment with other psychotropic drugs. The citalopram dose should therefore ideally be individualized by therapeutic drug monitoring.

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